Biomedical researchers in the 21st century work in the epicenter of an explosion in the understanding of human disease. The complete sequences of relevant genomes, like the human and various infectious organisms, lay the foundation for the next steps in probing molecular mechanisms of disease. Broad Institute researchers recognized at an early stage of this revolution that the perturbation of the cellular pathways that underlie phenotypic changes with small molecules will make it possible to dissect cell circuitry and disease biology, thus enabling a path forward to correcting human diseases. We have operated a Screening Facility in a production mode over the past ten years in an open data-sharing environment, created the first comprehensive and public small-molecule database and analysis environment containing over 20 million binding and assay-well measurements, a novel chemical biology information model and many powerful analysis tools, and, in 2007, made a substantial investment in personnel, screening automation, LIMS and robotics that has substantially increased these already significant production capabilities. This screening facility resides within a rich environment focused on small molecules and small-molecule screening integrated with disease biology and genome biology. We propose here a plan to operate a Comprehensive Screening Center at the Broad Institute of Harvard and MIT (BCSC), leveraging and complementing existing organizational and infrastructure initiatives by collaborating with a wider MLPCN research community. [unreadable] Impact on human health. The proposed Comprehensive Screening Center will generate many smallmolecule probes of human disease, including but not limited to cancer, schizophrenia, malaria, tuberculosis, and diabetes. The probes are outstanding starting points for the development of novel therapeutics. The Center will also provide early stage optimization of the probes so as to understand their potential for treatment and to increase the probability that they can lead to safe and effective therapeutics in the future. All data will be made publicly available, which will enable more therapeutic discovery efforts than would be possible otherwise. [unreadable] [unreadable] [unreadable]